Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke

Ann Neurol. 2013 Jan;73(1):129-35. doi: 10.1002/ana.23734. Epub 2012 Nov 28.

Abstract

Targeting newly identified damage pathways in the ischemic brain can help to circumvent the currently severe limitations of acute stroke therapy. Here we show that the activity of 12/15-lipoxygenase was increased in the ischemic mouse brain, and 12/15-lipoxygenase colocalized with a marker for oxidized lipids, MDA2. This colocalization was also detected in the brain of 2 human stroke patients, where it also coincided with increased apoptosis-inducing factor. A novel inhibitor of 12/15-lipoxygenase, LOXBlock-1, protected neuronal HT22 cells against oxidative stress. In a mouse model of transient focal ischemia, the inhibitor reduced infarct sizes both 24 hours and 14 days poststroke, with improved behavioral parameters. Even when treatment was delayed until at least 4 hours after onset of ischemia, LOXBlock-1 was protective. Furthermore, it reduced tissue plasminogen activator-associated hemorrhage in a clot model of ischemia/reperfusion. This study establishes inhibition of 12/15-lipoxygenase as a viable strategy for first-line stroke treatment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Arachidonate 12-Lipoxygenase / metabolism*
  • Arachidonate 15-Lipoxygenase / metabolism*
  • Female
  • Humans
  • Lipoxygenase Inhibitors / administration & dosage
  • Lipoxygenase Inhibitors / therapeutic use*
  • Male
  • Mice
  • Middle Aged
  • Stroke / drug therapy*
  • Stroke / enzymology*
  • Treatment Outcome

Substances

  • 12-15-lipoxygenase
  • Lipoxygenase Inhibitors
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase